Taxol and Taxotere and their analogues of general formula: ##STR1## which exhibit remarkable anticancer and antileukaemia properties, constitute remarkable chemotherapeutic agents for the treatment of a number of cancers such as, for example, cancers of the breast, of the prostate, of the colon, of the stomach, of the kidney, of the testicles and more especially cancer of the ovary.
In particular, in the general formula (I), Ar may denote an optionally substituted phenyl radical, R may denote a hydrogen atom or an acetyl radical or an N-substituted carbamoyl radical, R' denotes a hydrogen atom or an N-substituted carbamoyl radical and R.sub.1 may denote a phenyl radical or a radical R.sub.2 --O-- in which R.sub.2 denotes an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or heterocyclyl radical.
Taxol corresponds to the product of general formula (I) in which Ar and R.sub.1 denote a phenyl radical and R denotes an acetyl radical and R' denotes a hydrogen atom, and Taxotere corresponds to the product of general formula (I) in which Ar denotes a phenyl radical, R and R' denote a hydrogen atom and R.sub.1 denotes a t-butoxy radical.
Taxol, which exists in the natural state in various species of yew, in which it is present in small quantities, is difficult to isolate without effecting the total destruction of the plant. For example, taxol can be isolated by the method of C. H. O. Huang et al. J. Natl. Prod. 49,665 (1986), which consists in treating ground bark of Taxus brevifolia with methanol, concentrating the extract, extracting the concentrate with dichloromethane, reconcentrating, dispersing the residue in a hexane-acetone mixture (1--1 by volume), purifying the soluble part by chromatography on a Florisil column to obtain crude taxol, which is purified by successive recrystallizations from methanol-water and hexane-acetone mixtures and then chromatography and further crystallization. The quantities of taxol which are thus extracted can represent from 0.005 to 0.017% of the part of the plant which is used.
Taxotere , which does not exist in the natural state, can be prepared by partial synthesis from 10-deacetylbaccatin III of formula: ##STR2## by processes which are described, for example, in U.S. Pat. Nos. 4,814,470 or 4,924,012 or in international application PCT WO 92/09589.
Taxol can also be prepared by processes which involve the use of 10-deacetylbaccatin III or by going through the Taxotere intermediate under the conditions described in U.S. Pat. No. 4,857,653 or by esterification of baccatin III under the conditions described in European Patents EP 400,971 or EP 428,376 or by esterification of 10-deacetylbaccatin III and acetylation under the conditions described in U.S Pat. No. 4,924,011.
The different varieties of yew (Taxus baccata, Taxus brevifolia, Taxus canadensis, Taxus cuspidata, Taxus floridana, Taxus media, Taxus wallichiana) contain taxane derivatives, the main ones of which are essentially taxol and 10-deacetylbaccatin III, the other derivatives being more particularly cephalomannin, 10-deacetylcephalomannin or baccatin III, optionally bonded to sugars.
Whereas taxol is present chiefly in the trunk and the bark, 10-deacetylbaccatin III is present essentially in the foliage. Furthermore, the content of 10-deacetylbaccatin III in the foliage is generally much higher than that of taxol, whether the latter be present in the bark, the trunk or in the foliage.
As a result, it is particularly important to be able to have access to 10-deacetylbaccatin III, which is essential for the preparation of much larger quantities of taxol than by direct extraction from yew, and for the preparation of Taxotere.
Extraction of 10-deacetylbaccatin III from yew foliage does not result in a total destruction of the plant, whose foliage can be employed again after each growth cycle.
In general, the known methods for extracting taxane derivatives present in the various parts of the yew (bark, trunk, roots, foliage etc.) require the use of long and costly chromatographic techniques which do not permit a complete and quantitative separation of the taxane derivatives initially present in the plant.
10-Deacetylbaccatin III can be obtained, in yields of about 300 mg per kg of foliage (Taxus baccata) by a process which uses wet grinding of the needles in ethanol, extraction with an organic solvent such as methylene chloride and successive chromatographies by the process which is described in U.S. Pat. No. 4,814,470.
The various constituents derived from taxane which are present in the various parts of the yew can also be separated by methods using reverse-liquid phase chromatography which are described in particular in international application PCT WO 92/07842. These processes consist essentially in treating the crude yew extracts by reverse liquid phase chromatography on an adsorbent on which the taxane derivatives are immobilized, in eluting the taxane derivatives and in isolating them. According to this process it is possible to isolate 200 mg of 10-deacetylbaccatin III from 1 kg of ground and dried foliage.